PROPOSAL SUMMARY Total knee arthroplasty (TKA) is one of the most common surgeries performed in the United States (US). Prosthetic joint infections (PJI) are the most serious complication of this procedure, with high morbidity to patients and a large economic burden to the healthcare system. Despite the frequency of TKAs being performed in the US and the adverse impact of PJIs, the incidence, organisms implicated in these infections, and the risk factors for development of PJI after TKA remain unknown in the US. To begin to address these knowledge gaps, we will assemble a national cohort of patients who underwent TKA within the Veterans Health Administration (VA), the largest integrated health system in the US. In our first aim, we will determine the incidence and microbiology of PJI within the first year after TKA and compare results to those who develop PJI more than a year after TKA. We will compare results across these two time periods because infections developing <12 months after joint replacement typically arise from the introduction of skin and commensal bacteria into the surgical incision during or shortly after the surgery, whereas infections occurring 12 months after joint replacement typically arise from hematogenous seeding or local trauma. This aim will identify the time period of highest PJI incidence, furthering our understanding of the pathophysiology of these infections, and will inform the choice of empiric antibiotic therapy for PJI that develop during these two periods. In our second aim, we will evaluate host and surgical factors associated with PJI, regardless of the time that PJI developed; in a secondary analysis, we will explore if there are differences in risk factors between early and late PJI. This aim will assess the relative strength of association of risk factors, which will guide future interventions to reduce PJI rates. These results will help determine the timing of highest risk of PJI after TKA, identify the subgroups of TKA patients at highest risk for PJI for closer monitoring, and inform clinicians’ empiric antibiotic treatment decisions during suspected PJI. In addition, the training provided by this award will afford the applicant with skills important for her development into an infectious diseases epidemiologist, with the goal of becoming an independent investigator. The proposed training plan includes advanced epidemiologic and biostatistical coursework in the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, as well as mentorship from researchers in epidemiology, biostatistics, infectious diseases, and orthopedic surgery.